Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/72—Two oxygen atoms, e.g. hydantoin
  • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members

Definitions

• the subject of the present invention is a process for splitting chiral hydantoins of general formula (I):
• R denotes a lower alkyl radical comprising from 1 to 5 carbon atoms, with a straight or branched chain;
• R denotes a phenyl radical optionally monodi- or trisubstituted by lower alkyl or alkoxy radicals or halogen atoms, identical or different, or a heteroaryl radical containing a ⁇ 7-membered ring in which the single heteroatom is l nitrogen, oxygen or sulfur, or an aralkyl radical in which the alkyl part comprises one or two carbon atoms and the aryl ring is a phenyl group optionally mono, di- or trisubstituted by lower alkyl or alkoxy radicals or halogen atoms, identical or different.
• optically active resolving agents often toxic or unstable, which are commercially available on an industrial scale in a form of very relative and / or expensive purity and that, in addition, there is no It is often proposed that only one enantiomeric form of the resolution agent.
• Kuepfer et al. J. Pharmacol. Exp. Ther. 221 (3), 590-7, 1982 and 230 (1), 28-33, 1984
• DCI Metaldopa
• R j is a methyl radical and R, a 3,4- dihydroxybenzyle.
• Other optically active amino acids are prime intermediates for the preparation of therapeutically active compounds.
• the enantiomers and the racemic of the amino acid in which R ⁇ is a methyl radical and R a 3, -dichlorobenzyl radical lead, after reduction by metallic or organometallic hydrides, to amino alcohols, some of which, N- drugs, described in document FR-A-86 01 295, have analgesic properties and are active on the central nervous system.
• optically active amino acids in which R ⁇ is an ethyl radical and JJ either a phenyl radical or a thienyl radical make it possible, after their reduction to amino alcohols, to obtain amino esters or amino ethers active on the gastrointestinal tract, like some of the compounds described in documents FR-A-2 643 369 and EP-A-0 297 782.
• the present invention makes it possible to remedy these drawbacks by proposing a splitting method which uses an optically active resolving agent in common use, ⁇ -methylbenzylamine, in the form of its (R) (+) and ( S) (-), both commercially available, and whose physico-chemical properties (solubility, boiling point) allow easy recovery and industrial recycling.
• the process according to the invention is essentially characterized in that it consists in dissolving the chiral hydantoin (I) to be split in an alcohol or an alkaline solution, in adding to the solution obtained one of the enantiomers of ⁇ -methylbenzylamine into defined proportion, then isolating the diastereoisomer salt obtained and treating it with an acid solution to crystallize the enantiomer of hydantoin (I) which is thus obtained under satisfactory yield and optical purity conditions.
• a first embodiment of the method according to the invention consists in dissolving the chiral hydantoin (I) to be split in an alcohol and then adding the enantiomer of ⁇ -methylbenzylamine in an amount of at least four molar equivalents for a mole of hydantoin to be split, to obtain the crystallization of the only diastereoisomer salt.
• this salt is treated with an excess of an acid solution to crystallize the purified enantiomer from the hydantoin (I) which is filtered.
• the isolated crystals reveal an optical purity of up to 97%, revealed by the commonly used analytical methods, namely the determinations of the rotary power and the melting point as well as the high performance liquid chromatography (HPLC) on a column of a support. appropriate chiral, these analyzes can be confirmed by other methods such as radiocrystallography and infrared spectrography.
• the alcohol used comprises from one to three carbon atoms and has a boiling point equal to or less than 125 ° C. under atmospheric pressure.
• methanol ethanol
• 2-methoxyethanol are particularly preferred.
• the acid solution used to treat the diastereoisomer salt is advantageously an aqueous solution of a strong mineral acid, and preferably a solution of hydrochloric acid, in particular a solution of concentration N to 5N.
• a second embodiment of the method according to the invention consists in dissolving the chiral hydantoin (I) to be split in an alkaline solution then in adding the enantiomer of ⁇ -methylbenzylamine at the rate of at least one molar equivalent for a mole of hydantoin to be split, in order to obtain the crystallization of a diastereoisomeric salt, then to treat the latter according to the procedure previously described to obtain an enantiomer of the hydantoin (I).
• the alkaline solution can be: - either an aqueous solution containing ammonia, a mineral hydroxide or a water-soluble organic base;
• the alkaline solution is an aqueous ammoniacal solution
• the alkaline solution is an aqueous solution of a mineral hydroxide
• the latter is preferably an alkali metal hydroxide and more particularly sodium hydroxide.
• the splitting is carried out in the presence of approximately 0.5 molar equivalent of sodium hydroxide and by adding one to three molar equivalents of the ⁇ enantiomer -methylbenzylamine.
• the process preferably used is that which involves a mineral hydroxide and an enantiomer of ⁇ -methylbenzylamine in an alkaline aqueous medium with which acetone is associated as preferred co-solvent, at a rate of 0.2 to 10 volumes for a volume of aqueous solution, mixing a volume of water with 0.5 to 2 volumes of acetone generally leading to satisfactory results.
• the enantiomer obtained is the dextrorotatory (+) PEHYD isomer.
• Example 2 By practicing according to the procedure of Example 1, from 0.01 mole of (+/-) PEHYD and 0.01 mole of (R) (+) ⁇ -methylbenzylamine, by varying the mole NaOH / moles (+/-) PEHYD ratio, the tests of Examples 3-a to 3-i are carried out, the conditions and results of which are indicated in the following table, the isolated enantiomer being (+) PEHYD.
• Examples 4-a and 4-b are carried out by modifying the amount of (R) (+) - ⁇ -methylbenzylamine used.
• the results of these tests compared to that of Example 3.g are indicated in the table below.
• (+/-) PEHYD Doubling of (+/-) PEHYD in aqueous sodium hydroxide solution, with acetone as co-solvent.
• 20.0 g (0.098 mole) of (+/-) PEHYD are dissolved in 200 ml of an acetone / water (V / V) mixture.
• 1.76 g (0.044 mole) of sodium hydroxide are added in pellets and then 12.2 g (0.098 mole) of (S) (-) ⁇ -methylbenzylamine.
• the suspension is stirred while heating gradually to obtain the complete dissolution of the reactants at 65 ° C., then the solution is cooled slowly to a temperature of approximately 40 ° C., at which crystallization begins. After having maintained this temperature for one hour to promote crystalline development, the medium is gradually cooled to 20-25 ° C, then left overnight with stirring.
• the insoluble material is filtered, washed with 100 ml of water and, with stirring and without exceeding 20 ° C, the suspension is acidified to pH 1 by the addition of 4.0 ml of concentrated hydrochloric acid, causing precipitation of The levorotatory enantiomer of PEHYD which is filtered, washed with water and then dried under vacuum at 50 ° C.
• the enantiomer obtained is (S) (-) 5- (2-thienyl) -5- ethyl hydantoin, which is filtered, washed with water and dried under vacuum at 50 ° C.
• the mixture is heated with stirring to a temperature between 65 and 70 ° C for 15 hours.
• the suspension is cooled with stirring to 10-15 ° C and left for 16 hours at this temperature.
• the insoluble material is filtered, washed with water and then with di-isopropyl ether before being dried under vacuum at 50 ° C. to constant weight.
• the mixture With stirring, the mixture is brought to reflux until the reactants are dissolved. 100 ml of water are then introduced while gradually heating the mixture to 70 ° C., then the solution is slowly cooled with stirring.
• the crystalline precipitate is filtered, washed with 2 times 100 ml of an acetone / water mixture 2-1 (vol / vol).
• the insoluble material is, as it is, suspended in 250 ml of water and the mixture is acidified to pH 1 by progressive addition of a solution of concentrated hydrochloric acid.
• the insoluble material is filtered and washed with water.
• the optical purity of the product determined by HPLC on an aliquot fraction is 98.6%.
• the wet product is recrystallized at reflux in

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Electrochromic Elements, Electrophoresis, Or Variable Reflection Or Absorption Elements (AREA)

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• 1990
  • 1990-11-16 FR FR9014487A patent/FR2669333B1/fr not_active Expired - Fee Related
• 1991
  • 1991-11-15 EP EP92900281A patent/EP0510168B1/de not_active Expired - Lifetime
  • 1991-11-15 AU AU90354/91A patent/AU9035491A/en not_active Abandoned
  • 1991-11-15 US US07/910,184 patent/US5326878A/en not_active Expired - Fee Related
  • 1991-11-15 JP JP04500426A patent/JP3125101B2/ja not_active Expired - Fee Related
  • 1991-11-15 WO PCT/FR1991/000906 patent/WO1992008702A1/fr active IP Right Grant
  • 1991-11-15 ES ES92900281T patent/ES2096066T3/es not_active Expired - Lifetime
  • 1991-11-15 CA CA002073762A patent/CA2073762A1/fr not_active Abandoned
  • 1991-11-15 AT AT92900281T patent/ATE147379T1/de active
  • 1991-11-15 DE DE69124088T patent/DE69124088T2/de not_active Expired - Fee Related

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